The objective of this research program is to define molecular mechanisms that regulate aberrant inflammatory events to identify targets for agonists, antagonists and/or therapeutic intervention in pathogenic conditions. In vitro models and experimental animal systems including gene targeting models (gene knockouts and transgenics) and models of genetic susceptibility to arthritis and other chronic inflammatory diseases provide opportunities to define pathogenesis. Administration of group A streptococcal cell wall peptidoglycan-polysaccharide complexes induces arthritis, liver fibrosis, and spleen cell anergy in genetically susceptible rodents and provides a model to explore all phases of an immune response and the consequences of its dysregulation. In addition, human conditions of chronic inflammatory disease in response to foreign implants, infectious pathogens or of unknown etiology are explored at the cellular, molecular and biochemical levels. An important objective of this research is to identify known and novel molecules expressed during the evolution of these debilitating inflammatory diseases. One mechanism for controlling these pathologic events is through oral tolerance and the induction of TGF-beta. In addition, regulation of the processes of inflammation and tissue destruction by both local and systemically targeted gene therapy may provide new insight into pathogenesis and therapeutic intervention.